3-9371378-A-G

Position:

• chr3-9371378-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001114092.2(THUMPD3):​c.649A>G​(p.Lys217Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: THUMPD3 NM_001114092.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50

Genes affected

THUMPD3 (HGNC:24493): (THUMP domain containing 3) Predicted to enable tRNA (guanine) methyltransferase activity. Predicted to be involved in tRNA methylation. Located in cytosol and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

THUMPD3-AS1 (HGNC:44478): (THUMPD3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09772092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THUMPD3	NM_001114092.2	c.649A>G	p.Lys217Glu	missense_variant	4/10	ENST00000452837.7	NP_001107564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THUMPD3	ENST00000452837.7	c.649A>G	p.Lys217Glu	missense_variant	4/10	1	NM_001114092.2	ENSP00000395893	P1
THUMPD3-AS1	ENST00000468186.5	n.2875+18912T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2023

The c.649A>G (p.K217E) alteration is located in exon 4 (coding exon 3) of the THUMPD3 gene. This alteration results from a A to G substitution at nucleotide position 649, causing the lysine (K) at amino acid position 217 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.0022	T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.57	.;.;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.0080	B;B;B
Vest4		0.19
MutPred		0.48		Loss of ubiquitination at K217 (P = 0.0041);Loss of ubiquitination at K217 (P = 0.0041);Loss of ubiquitination at K217 (P = 0.0041);
MVP		0.63
MPC		0.070
ClinPred		0.27	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2032025244; hg19: chr3-9413062;